Therapeutic sulfonamide compositions



Patented Oct. 11, 1949 OFFICE THERAPEUTIC SULFONAMIDE COMPOSITIONS David Lehr, New York, N. Y.

No Drawing.

Application February 6, 1948, Serial No. 6,812

4 Claims. (01. 167-515) This invention relates to novel compositions having new and valuable therapeutic properties.

A principal object of the invention is to provide sulfonamide drugs of lower toxicity, more complete utilization and increased effectiveness, by combining two or more of these compounds.

A particular object of the invention is the provision of sulfonamide drug compositions which will eliminate or substantially decrease the kidney damage attending the therapeutic use of the sulfonamide compounds heretofore available.

In the systematic administration of sulfonamide drugs, it is the endeavor of the physician to produce and maintain a therapeutically effective concentration of the drug in the blood and other body fluids and tissues of the patient. However, a limit is placed on the concentrations of the drug which may be maintained in the body because of certain toxic reactions which increase in frequency and severity with increasing sulfonamide blood concentrations in the body, although there may be considerable variations with regard to the particular sulfonamide employed and also with regard to the individual patient treated. These untoward reactions constitute a significant drawback in the therapeutic employment of sulfonamides.

One of the most frequent and most serious of the toxic reactions encountered in the administration of sulfonamide drugs is renal obstruction. This has been shown to be due to the deposition of si'ilfonamide crystals and the formation of solid sulfonamide concrements in the urinary tract, which adversely afiectsthe kidney functions both by, mechanical obstruction and by damaging the kidney parenchyma.

I have found that renal toxicity due to the formation of renal concrements can be greatly reduced or eliminated without decreasing the therapeutically desirable total concentrations of the drugs, or even with an actual increase in drug concentrations, and that all desirable therapeutic effects may be obtained to the same degree or even to an increased degree by means of mixtures of two or more sulfonamide drugs of different molecular constitution.

Of particular value are mixtures of two or more homologous sulfanilamidopyrimidines, such as sulfadiazine- (2-sulfanilamidopyrimidine) sulfamerazine (2-sulfanilamido-4-methylpyrimidine), and sulfamethazine (2 sulfanilamido 4,6 dimethylpyrimidine). By means of the mixtures of sulfonamide drugs of the invention, it is possible to maintain highly effective concentrations of the centration of any single drug in the mixture from closely approaching levels at which, in accordance with general clinical experience, renal toxic effects are known to appear. If desired, to obtain a special therapeutic effect or to still further reduce the concentration of one or more of the drugs in the body fluids while preventing the condrugs in the composition, mixtures of other sulfonamide drugs, such as N -substitution products suchas sulfacetimide, sulfathiazole, and sulfaguanidine, or N N -substitution products such as su'ccinylsulfathiazole, with two or more of the homologous sulfonamidopyrimidines may be provided. Of particular usefulness are mixtures of substantially equal proportions of sulfadiazine and sulfamerazine with sulfacetimide (N -acetylsulfanilamide) in amounts ranging from about 0.5 to about 5 parts by weight to each part of the combined sulfadiazine and sulfamerazine.

In general, the most effective results in reduction of renal toxicity are obtained when the individual sulfonamide components of the mixture are present in approximately equimolecular proportions, although the beneficial effects of the invention may be obtained when the proportions of the sulfonamide components vary over the range of 1:1 to 1:3 molar equivalents and the term substantially equal proportions as used herein is intended to express this range of proportions.

Likewise, no fatalities were obtained on the intraperitoneal injection of mixtures of 0.5 grams per kilogram body weight each of sulfadiazine and sulfamerazine with sulfacetimide added in amounts of 0.5, 1.0, 2.0, 3.75, and 5.0 grams per kilogram body weight.

Tests have also shown that on the administration of mixtures of sulfadiazine and sulfamerazine the blood levels and urine concentrations of the mixed drugs are higher than would be expected from the, values obtained with the drugs when administered singly and determination of total urinary elimination of the drugs shows that excretion of the mixture is far more complete than from either compound administered singly in equal amounts. When sulfacetimide is added to the mixtures of sulfadiazineand sulfamerazine the total urinary elimination is not only higher thanfrom any one of the three compounds administered singly but also significantly more complete than from a mixture of sulfadiazine and sulfamerazine.

The remarkable reduction in toxicity provided by the compositions of the invention is strikingly illustrated by the following series of toxicity tests on albino rats. In the tests the drugs in the form 3 of their sodium salts were injected into the rats in the amounts indicated, in single intraperitonea-l injections:

aaeaive Acute Tokricity of Sulfadiazine (SD), Sulfamerazine (SMD) and Suljace imide (SAc) singly and in combination It will be noted that the mixture which consisted of one-half of the LDas of suliadiazine, onehalf of the LD52 of sulfamerazine, and more than one-half of the LD83 of sulfacetimide caused no fatality at all.

Some of the sulfonamide compositions of the invention show, in addition to the decreased renal toxicity, 2. definite improvement in the therapeutic efiect. In other words, sufonamide mixtures may show a better curative effect than any one of the component drugs. This conclusion is derived from clinical observations. It is confirmed by in vitro antibacterial studies which disclose that, for example, mixtures of equal parts of sulfadiazine and sulfamerazine, are, in many instances, significantl y more eifective against strep, hemolyticus, staph. aureus, pneumococcus and E. coli than either of the two drugs used alone in the same total concentration.

The compositions of the invention may be dispensed in powder form, compressed into tablets, in solution (particularly in the form of the sodium salts) or in any other desirable form, and any desirable and compatible .substances may be added thereto to aid or improve the compounding, dispensing or administration of the compositions. The compositions defined in the claims hereof are intended to include the salts of the defined components.

This application is a continuation-in-part of my application Serial No. 611,445, filed August 18, 1945.

I claim:

1. A therapeutic composition prepared for the internal administration of sulfonamide drugs consisting of a mixture of substantially equal amounts of at least two p-aminobenzenesulfonamide compounds selected from .the group consisting of 2-sufanilamidopyrimidine and homologues thereof, the amount of each component in each dose being substantially less than the full dosage of such componentof the mixture that would be given if such component were given alone, whereby the renal toxicity is substantially reduced without reduction of the therapeutic efiect as compared with the toxicity and therapeutic effect of each of said mixture components when given singly in full dosage.

2. A therapeutic composition prepared for the internal administration of sulfonamide drugs consisting of a mixture of substantially equal amounts of 2-sulfanilamidopyrimidine and 2-sulfanilamido-4-methylpyrimidlne, the amount of each component in each dose being substantially less than the full dosage of such component of the mixture that would be given if such component were given alone, whereby the renal toxicity is substantiallly reduced without reduction of the therapeutic efiect as compared with the toxicity and the therapeutic effect of each of said mixture components when given singly in full dosage.

3. A therapeutic composition prepared for the internal administration of sulfonamide drugs consisting of a mixture of substantially equal amounts of at least two p-aminobenzenesulfonamide compounds selected from the group consisting of 2-sulfanilamidopyrimidine and homologues thereof and from about 0.5 to about 5 parts by weight of N -acetylsuianilamide to each part of the combined 2-sulfanilamidopyrimidine compounds, the amount of each component in each dose being substantially less than the full dosage of such component of the mixture that would be given if such component were given alone, whereby the renal toxicity is substantially reduced without reduction of the therapeutic efiect as compared with the toxicity and therapeutic effect of each of said mixture components when given singly in full dosage.

4. A therapeutic composition prepared for the internal administration of sulfonamide drugs consisting of a mixture of substantially equal amounts of 2-sulfanilamidopyrimidine and 2- sulfanilamido-4-methylpyrimidine, and from 0.5 to about 5 parts by weight of N -acetylsulfanilamide to each part of the combined 2-sulfanilamide-pyrimidine compounds, the amount of each component in each dosebeing substantially less than the full dosage of such component of the mixture that would be given if such component were given alone, whereby the renal toxicity is substantially reduced without reduction of the therapeutic effect as compared with the toxicity and therapeutic efiect of each of said mixture components when given singly in full dosage.

DAVID LEHR.

REFERENCES CITED The following references are of record in the file of this patent:

J. Amer. Medical Association, August 9, 1941, page 409.

Annals of Internal Medicine, September 1941, pages 436 to 439.

British Medical J August 16, 1941, page 221.

J. Amer. Pharm. Assoc., Scientific Edition, May 1943, page 142.

Canadian Med. Assoc. J January 1943, pages 13 to 18;

Committee on Medical Research of the O.S.R.D., Contract No. OEM, cmr 300, Report No.

5. February 3, 1944, page 1. 43.)

(Copy in Division Certificate of Correction Patent No. 2,484,175 October 11, 1949 DAVID LEHR It is hereby certified that errors appear in the printed specification of the above numbered patent requiring correction as follows:

Column 3, line 60, for sufanilamidopyrimidine read sulfanilamidopyrim'idine; column 4, line 22, for N -acetylsufanilamide read N-acetyls'zdfan'ilamide;

and that the said Letters Patent should be read with these corrections therein that the same may conform to the record of the case in the Patent Oflice.

Signed and sealed this 7th day of February, A. D. 1950.

THOMAS F. MURPHY,

Assistant C'ommz'ssioner of Patents. 

